Surg Today DOI 10.1007/s00595-014-0943-z
ORIGINAL ARTICLE
Clinicopathological features, postoperative survival and prognostic variables for cancer-related survival in patients with mucinous colorectal carcinoma Sei-ichiro Jimi • Masayuki Hotokezaka • Takuto Ikeda • Shuichiro Uchiyama • Hideki Hidaka • Naoki Maehara • Hidenobu Ishizaki • Kazuo Chijiiwa
Received: 22 October 2013 / Accepted: 1 April 2014 Ó Springer Japan 2014
Abstract Purpose To investigate the clinicopathological features and postoperative survival of patients with mucinous colorectal carcinoma (MC) and to identify the factors related to long-term survival. Methods Twenty-three patients who had undergone resection for MC at Miyazaki University Hospital from 1991 to 2006 were followed up for at least 5 years or until death. The effects of the clinicopathological variables on the 5-year cancer-specific survival were assessed by the univariate analyses. These patients’ clinicopathological data were compared with those of 403 non-mucinous carcinoma (NMC) patients (102 well-differentiated adenocarcinomas, 301 moderately differentiated adenocarcinomas). Results The 5-year cancer-specific survival rate was significantly worse in MC (56.2 %) than in NMC (73.8 %; p = 0.008) cases. Univariate analyses showed the T factor, lymph node metastases, liver metastases, metastases to the distant peritoneum, remote metastases and curative resection to be significant factors predicting the survival. However, there were no significant differences in the postoperative survival in patients with stage II–IV disease. The rates of metastases to the distant peritoneum, M1, T4, a tumor size C5 cm and non-curative resection were higher in MC than in NMC patients.
S. Jimi (&) M. Hotokezaka T. Ikeda S. Uchiyama H. Hidaka N. Maehara H. Ishizaki K. Chijiiwa Department of Surgery 1, Miyazaki University School of Medicine, Miyazaki, Japan e-mail: [email protected] M. Hotokezaka Department of Surgery, Junwakai Memorial Hospital, Miyazaki, Japan
Conclusions Patients with MC had advanced stage cancer, especially with metastases to the distant peritoneum, more frequently than did the patients with NMC. To improve the survival of these patients, it is therefore important to detect MC at an early stage and to perform curative resection. Keywords Colorectal neoplasms Mucinous colorectal cancer Survival
Introduction Mucinous colorectal carcinoma (MC) is a histological subtype of colorectal cancer characterized by extracellular mucin production [1]. MC accounts for 5–15 % of all colorectal cancers [1–11]. MC is usually in a more advanced stage when it is diagnosed than well- or moderately differentiated adenocarcinoma, which is considered to be one reason for the worse prognosis of patients with MC than patients with non-mucinous colorectal carcinoma (NMC) [5, 8, 9, 12, 13]. However, the postoperative survival for MC patients in each stage is unclear, and the factors related to the survival of patients with MC have not been well studied. The aim of this retrospective study was to investigate the clinicopathological features and postoperative survival of patients with MC, and to identify the factors related to their long-term survival.
Patients and methods From 1991 to 2006, 446 patients at Miyazaki University Medical Hospital underwent surgery for colorectal carcinoma. Tumor resection for MC was confirmed in 26
123
Surg Today
patients, 23 of whom had verified survival data. The hospital maintains a database, and the medical records of all 23 patients were retrieved from this database. The database record includes data on the sex, age, past history, major medical problems, tumor location, maximum tumor size, histopathological stage, venous invasion and depth of wall invasion. The preoperative serum carcinoembryonic antigen (CEA) levels were obtained from the medical records. Data pertaining to the 23 MC patients were retrieved by reviewing the patients’ individual records, and variables were classified according to the TNM system [14]. The P factor refers to peritoneal metastasis, and was subclassified as follows: P0, no peritoneal metastasis; P1, metastasis localized in the adjacent peritoneum; P2, limited metastasis to the distant peritoneum and P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma [15]. P2 and P3 were both considered to indicate that the patient had metastasis to the distant peritoneum. The curability of surgical resection was determined at the end of surgery. When there was no residual cancer, the patient was determined to have undergone a curative surgery. When residual cancer was identified, then the patient was determined to have undergone non-curative surgery. Almost all patients returned to the hospital for followup. Telephone contact was made with patients, if necessary, to obtain up-to-date information. The effects of the clinicopathological variables, including the age, sex, number of metastatic lymph nodes, depth of wall invasion and preoperative serum CEA levels on survival were analyzed.
Statistical analyses The means were compared by Student’s t test, and 2 9 2 proportions were compared using Fisher’s exact test, while 8 9 2 and 4 9 2 proportions were tested by the v2 test [16]. The cancer-specific survival curves were generated using the Kaplan–Meier method [17]. To identify prognostic factors for survival, differences were compared by the log-rank test. A value of p \ 0.05 was considered to be significant. All statistical analyses were performed using the SPSS version 14.0J for Windows software program (SPSS Inc., Chicago, IL, USA).
Results In total, 23 patients with MC were included in the final analysis (14 males, 9 females; median age 65.7 years; age range 40–78 years). The mean follow-up period was 1,737 days (range 54–4,735 days). Cancer-related deaths
123
occurred in 12 cases. The 5-year cancer-specific survival rate was 56.2 %. Three patients could not be contacted because more than 5 years had passed since their surgeries. A total of 403 patients with NMC were included in the final analyses (269 males, 134 females; median age 65.7 years; age range 20–92 years). The mean follow-up period of the NMC patients was 2,293 days (range 7–4,677 days). Cancer-related deaths occurred in 121 cases. The 5-year cancer-specific survival rate was 73.8 %. A total of 17 patients could not be contacted because more than 5 years had passed since their surgeries. The overall compliance rate was 95.5 %. The background data were compared by Fisher’s exact test, the v2 test and Student’s t test, and the results are shown in Table 1. The rate of right-sided colon carcinoma was significantly higher in the MC than in the NMC group. The mean size of the tumor in the MC patients was 7.22 cm (range 3–20 cm); the mean size of the tumor in the NMC patients was 4.67 cm (range 0.5–28 cm). The mean size of the tumor was significantly greater in the MC patients than in the NMC patients (p = 0.008). There was also a significant difference in the rate of tumors larger than 5 cm between these groups. Nine MC patients had T4 tumors. Lymph node involvement was noted in 13 patients. Fifteen of the 23 patients presented at an advanced stage (five patients at stage III and 10 at stage IV). The rates of venous invasion, liver metastases and high CEA levels were not significantly different between the MC and NMC cases. Of the 23 patients with MC, 10 presented with distant metastases at the time of diagnosis. Nine patients had peritoneal dissemination, followed by liver metastases in five patients and a distant lymph node in one patient. The rates of T4 disease, the presence of peritoneal dissemination, M1 disease and advanced stage disease were significantly higher in the MC group than in the NMC group (Table 1). The rate of patients with non-curative resection was also higher in the MC than in the NMC patients. Peritoneal dissemination was usually classified by subtype according to the Japanese Classification of Colorectal Carcinoma. The 5-year survival rate of patients with P2 or P3 was 0 % in both the MC and NMC groups (Table 2). The 5-year survival rate of patients with P0 or P1 was also not significantly different between the MC and NMC groups (p = 0.302). The incidence of P2 or P3 disease was higher in the MC patients than in the NMC patients (Table 1). The results of a univariate analysis are shown in Table 3. The age, sex, location of the primary tumor, presence of venous invasion, preoperative serum CEA level, and size of the tumor had no significant effects on the survival. The univariate analysis showed that the presence
Surg Today Table 1 Clinical and pathological factors
Table 1 continued
MC (n = 23)
NMC (n = 403)
p value
Male
14
269
Female
9
134
0.355
65.7 (40–78)
65.7 (20–92)
0.987
Sex
Mean age (range, years)
15
242
C70 years
8
161
Right side
11
91
Left side
12
312
T1
0
50
T2
3
73
T3
11
219
T4
9
61
0.009
Tumor invasion depth
340
9
63
0.008
MC mucinous colorectal carcinoma, NMC non-mucinous colorectal carcinoma, CEA carcinoembryonic antigen The P factor was subclassified as follows: P0, no peritoneal metastasis, P1, metastasis localized to the adjacent peritoneum, P2, limited metastasis to the distant peritoneum or P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma b TNM, TNM classification of malignant tumors
No. of cases
0.012
5-year survival rate (%)
MC P0
14
78.6
P1
4
33.3
P2
1
0
355
P3
4
0
48
P0 or P1
18
71.8
P2 or P3
5
0
Negative
10
246
Positive
13
157
18 5
0.074
0.144
Peritoneal dissemination Negative
14
383
Positive
9
20
NMC \0.001
P factor subclassa P0 or P1
15
389
P2 or P3
5
14
Negative
13
334
Positive
10
69
I
1
109
II
7
123
III
5
99
10
72
0.021
Remote metastasis 0.004
TNM stageb
6
111
Positive
17
292
0.548
4.67 (0.5–28)
0.008
Maximum size of tumor (range, cm) 7.22 (3.0–20.0)
P0
383
77.0
P1
6
50.0
P2 P3
10 4
0 0
P0 or P1
389
76.3
P2 or P3
14
0
The P factor was subclassified as follows: P0, no peritoneal metastasis, P1, metastasis localized to the adjacent peritoneum, P2, limited metastasis to the distant peritoneum or P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma
0.008
Negative
\5.0 cm
8
242
C5.0 cm
15
161
0.015
275 (2.0–5630)
175 (0.7–15184)
0.697
\5 ng/mL
8
196
C5 ng/mL
15
207
CEA
14
Non-curative
Table 2 The 5-year survival rates stratified by the P factor subclass
Lymph node metastasis
IV Venous invasion
Curative
p value
a
0.397
Location
Positive
NMC (n = 403)
Resection
\70 years
Liver metastasis Negative
MC (n = 23)
0.140
of T4 disease (p = 0.004), lymph node metastases (p = 0.044), liver metastases (p = 0.003), peritoneal dissemination (p \ 0.001), P2 or P3 disease (p \ 0.001), remote metastases (p \ 0.001), and curative resection (p \ 0.001) were significant factors affecting the survival. The 5-year overall cancer-specific survival rate was significantly worse in the MC patients (56.2 %) than in the well- or moderately differentiated NMC patients (73.8 %; p = 0.008) (Table 4). On the other hand, there was no significant difference in the postoperative survival in the patients with stage II, III and IV disease between the MC and NMC patients (Table 4). The survival of the patients in
123
Surg Today Table 3 The results of the univariate analysis for prognostic factors for mucinous carcinoma n
5-year survival (%)
Table 4 The survival of the MC and NMC patients stratified by stage n
5-year survival (%)
p value
p value Overall
Sex Male
MC 14
57.1
9
55.6
\70 years
15
59.3
C70 years
8
50.0
Location Right side
11
36.4
Left side
12
75.0
14
78.6
9
22.2
Negative
10
80.0
Positive
13
36.9
Negative
18
71.8
Positive
5
0.0
Female
NMC 0.783
Age
NMC
NMC
Tumor invasion depth T2 and T3 T4 Lymph node metastasis
0.008
1 109
100 96.1
Not assessed
7
100
123
82.5
0.170
5 99
60.0 79.5
0.182
MC
10
20.0
NMC
72
16.7
Stage III MC NMC
0.004
73.8
Stage II MC
0.162
56.2
Stage I MC
0.978
23 403
Stage IV 0.181
0.044
Liver metastasis 0.003
Peritoneal dissemination Negative
14
78.6
Positive
9
22.2
15
71.8
5
0
P factor subclass P0 or P1 P2 or P3
\0.001
\0.001
Remote metastasis Negative
13
84.6
Positive
10
20.0
\0.001
Venous invasion Negative
6
66.7
Positive
17
52.3
0.541
Maximum size of tumor \5.0 cm
8
33.3
C5.0 cm
15
66.7
\5 ng/mL
8
75.0
C5 ng/mL
15
40.0
0.067
14 9
85.7 0.0
\0.001
0.166
CEA
Resection Curative Non-curative
stage I could not be compared because there was only one MC case with stage I disease.
Discussion In this study, the clinicopathological features and survival of MC patients were assessed. The definition of MC is the
123
presence of a mucosal pool generated by the tumor. Symonds et al. [1] first reported that the tumors classified as MC were composed of glands secreting lakes of mucus deep within the infiltrating portion of the tumor. According to the WHO definition [18], MC is an adenocarcinoma in which a substantial amount of mucin ([50 % of the tumor) is retained within the tumor. The incidence of MC is about 5 % in Asian countries, such as Japan and Singapore [6–11], while the incidence of MC is about 10–15 % in Western countries [1–4, 19]. Because the 5-year survival rate of MC patients is 33–60 %, MC is considered to be a tumor with a poor prognosis [5, 8, 9, 12, 13]. However, there have been a few reports showing that the survival of MC patients was not significantly different from that of NMC patients [1, 4, 19]. In the present study, the overall 5-year survival rate of MC was 56.2 %, which was significantly worse than that for NMC. The overall survival of MC patients in each stage has not been adequately reported. Ikeda et al. [8] reported that the prognosis of MC was poorer than that of NMC at both stage II and stage III. Pihl et al. [3] reported the survival of Dukes A and C MC patients to be significantly worse than that of NMC patients. On the other hand, Consorti et al. and Berg et al. reported that there were no significant differences between MC and NMC patients at each stage [2, 20]. In the present study, there were no significant differences in the postoperative survival between MC and NMC patients in stages II, III and IV. The rate of patients in an advanced stage at presentation is high in primary MC cases [5, 8, 9]. Lymph node metastases or distant metastases are seen in most patients at the time of diagnosis [7, 21]. Spread throughout the
Surg Today
peritoneal cavity and lymph nodes is frequently seen, but distant hematogenous metastases, especially in the liver and lung, are uncommon [7]. The rate of stage III and stage IV disease was significantly higher in the MC than in the NMC patients in the present study (Fisher’s exact test). It has been suggested that the poorer prognosis of MC is related to the stage of the disease and to the extent of spread, but not to the mucinous histological type [5, 7–9, 19], and this appears to correlate with our present findings. The incidence of MC is higher in the right side of the colon than in the left side of the colon from the splenic flexure [2, 5, 22, 23]. Many reports have found that the incidence of MC was higher in younger patients than in older patients [4, 5, 11, 24, 25]. In the present study, there were no patients younger than 40 years, but there was a higher rate of right-sided cancer in the MC group than in the NMC group. In our previous report, the patients with P0 or P1 dissemination survived longer after surgery than did the patients with peritoneal metastasis, who were classified as P2 or P3 [26]. In the present study, the 5-year survival rate of the patients classified as P2 or P3 was 0 % in both the MC and NMC groups. The 5-year survival rate of the patients classified as P0 or P1 was also not significantly different between the MC and NMC groups. The incidence of P2 or P3 disease was higher in the MC than in the NMC groups (p = 0.021). Patients with MC more frequently had peritoneal metastasis to the distant peritoneum than did the patients with NMC, and thus the patients with MC had a worse prognosis than the patients with NMC, even though there were no significant differences between the patients in the two groups in each stage (for stages II–IV). The present univariate analyses identified five significant prognostic factors for the survival of patients with MC: the depth of tumor wall invasion (T factor), presence of lymph node metastases, presence of liver metastases, presence of peritoneal dissemination and the presence of non-curable remote metastases (M factor). The CEA level and the size of the primary tumor were not prognostic factors for the MC group. Although the tumor size was significantly larger in the MC patients than in the NMC patients (Student’s t test and Fisher’s exact test), the tumor size was not a prognostic factor for MC in the univariate analyses in the present study. Kubota et al. [10] also reported that liver metastases and the depth of tumor invasion were prognostic factors for MC. MC of the rectum demonstrates a poorer response to standard preoperative chemoradiotherapy than NMC [27]. However, recent advances in adjuvant chemotherapy have further improved the disease-free survival after curative surgery for colon cancer [28], but an effective regimen for MC has not yet been found.
The postoperative survival was not significantly worse for the MC patients than for the NMC patients in each stage. However, the patients with MC had advanced stage cancer, especially with advanced peritoneal dissemination, more frequently than did the patients with NMC at the time of diagnosis. This seems to be an important factor associated with the poor prognosis after surgery in patients with MC. To improve the survival of these patients, it is important to detect MC at an early stage and to perform curative resection. Conflict of interest conflicts of interest.
Sei-ichiro Jimi and the co-authors have no
References 1. Symonds DA, Vickery AL. Mucinous carcinoma of the colon and rectum. Cancer. 1976;37:1891–900. 2. Consorti F, Lorenzotti A, Midiri G, Paola M. Prognostic significance of mucinous carcinoma of colon and rectum: a prospective case–control study. J Surg Oncol. 2000;73:70–4. 3. Pihl E, Narin RC, Hughes ESR, Cuthbertson AM, Rollo AJ. Mucinous colorectal carcinoma immunopathology and prognosis. Pathology. 1980;12:439–47. 4. Minsky BD, Mies C, Rich TA, Recht A, Chaffey JT. Colloid carcinoma of the colon and rectum. Cancer. 1987;60: 3103–12. 5. Wu CS, Tung SY, Chen PC, Kuo YC. Clinicopathological study of colorectal mucinous carcinoma in Taiwan: a multivariate analysis. J Gastroenterol Hepatol. 1996;11:77–81. 6. Kanemitsu Y, Kato T, Hirai T, Yasui K, Morimoto T, Shimizu Y, et al. Survival after curative resection for mucinous adenocarcinoma of the colorectum. Dis Colon Rectum. 2003;46: 160–7. 7. Yamamoto S, Mochizuki H, Hase K, Yamamoto T, Ohkusa Y, Yokoyama S, et al. Assessment of clinicopathological features of colorectal mucinous adenocarcinoma. Am J Surg. 1993;166: 257–61. 8. Ikeda S, Shimizu Y, Fujimori M, Ishizaki Y, Kurihara T, Okajima T, et al. Immunohistochemical and mutational analyses of betacatenin, ki-ras, and p53 in two subtypes of colorectal mucinous carcinoma. Clin Cancer Res. 2003;9:5660–5. 9. Nozoe T, Anai H, Nasu S, Sugimachi K. Clinicopathological characteristics of mucinous carcinoma of the colon and rectum. J Surg Oncol. 2000;75:103–7. 10. Kubota K, Akasu T, Fujita S, Sugihara K, Moriya Y, Yamamoto S. Clinical and pathological prognostic indicator with colorectal mucinous carcinomas. Hepatogastroenterology. 2004;51:142–6. 11. Du W, Mah JT, Lee J, Sankila R, Sankaranarayanan R, Chia KS. Incidence and survival of mucinous adenocarcinoma of the colorectum: a population-based study from an Asian country. Dis Colon Rectum. 2004;47:78–85. 12. Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JB Jr, Ray JE. Mucinous carcinoma: just another colon cancer? Dis Colon Rectum. 1993;36:49–54. 13. Okuno M, Ikehara T, Nagayama M, Kato Y, Yui S, Umeyama K. Mucinous colorectal carcinoma: clinical pathology and prognosis. Am Surg. 1988;54:681–5. 14. Sobin LH, Gospodarowicz MK, Wittekind CH, editors. TNM classification of malignant tumours (UICC). 7th ed. West Sussex: Wiley; 2009.
123
Surg Today 15. Japanese Society for Cancer of the Colon and Rectum, editors. Japan Classification of colorectal carcinoma. 2nd English ed. Tokyo: Kanehara &Co., Ltd; 2009. 16. Agresti A. A survey of exact inference for contingency tables. Stat Sci. 1992;7:131–77. 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81. 18. Jass JR, Sobin LH. Histological type of intestinal tumors. Berlin: Springer-Verlag; 1989. 19. Umpleby HC, Ranson DL, Williamson RCN. Peculiarities of mucinous colorectal carcinoma. Br J Surg. 1985;72:715–8. 20. Berg JW, Godwin JD. The epidemiologic pathology of carcinoma of the large bowel. J Surg Oncol. 1974;6:381–400. 21. Parham D. Colloid carcinoma. Ann Surg. 1923;77:90–105. 22. Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Luciana BA, Renato C, et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann Surg Oncol. 2008;15:1429–39.
123
23. Halvorsen TB, Seim E. Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariant analysis. J Clin Pathol. 1988;41:1068–72. 24. Messerini L, Ciantelli M, Baglioni S, Palomba A, Zampi G, Papi L. Prognostic significance of microsatellite instability in sporadic mucinous colorectal cancers. Hum Pathol. 1999;30:629–34. 25. Keswani SG, Bolye MJ, Maxwell JP 4th, Mains L, Wilks SM, Hunt JP, et al. Colorectal cancer in patients younger than 40 years of age. Am Surg. 2002;68:871–6. 26. Hotokezaka M, Jimi S-I, Hidaka H, Ikeda T, Uchiyama S, Nakashima S, et al. Factors influencing outcome after surgery for stage IV colorectal cancer. Surg Today. 2008;38:784–9. 27. Shin US, Yu CS, Kim JH, Kim TW, Lim SB, Yoon SN, et al. Mucinous rectal cancer: effectiveness of preoperative chemoradiotherapy and prognosis. Ann Surg Oncol. 2011;18:2232–9. 28. Andre T, Cormier JN, Krishnan S, Yao J, Staerkel GA, Lupo PJ, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.
ORIGINAL ARTICLE
Clinicopathological features, postoperative survival and prognostic variables for cancer-related survival in patients with mucinous colorectal carcinoma Sei-ichiro Jimi • Masayuki Hotokezaka • Takuto Ikeda • Shuichiro Uchiyama • Hideki Hidaka • Naoki Maehara • Hidenobu Ishizaki • Kazuo Chijiiwa
Received: 22 October 2013 / Accepted: 1 April 2014 Ó Springer Japan 2014
Abstract Purpose To investigate the clinicopathological features and postoperative survival of patients with mucinous colorectal carcinoma (MC) and to identify the factors related to long-term survival. Methods Twenty-three patients who had undergone resection for MC at Miyazaki University Hospital from 1991 to 2006 were followed up for at least 5 years or until death. The effects of the clinicopathological variables on the 5-year cancer-specific survival were assessed by the univariate analyses. These patients’ clinicopathological data were compared with those of 403 non-mucinous carcinoma (NMC) patients (102 well-differentiated adenocarcinomas, 301 moderately differentiated adenocarcinomas). Results The 5-year cancer-specific survival rate was significantly worse in MC (56.2 %) than in NMC (73.8 %; p = 0.008) cases. Univariate analyses showed the T factor, lymph node metastases, liver metastases, metastases to the distant peritoneum, remote metastases and curative resection to be significant factors predicting the survival. However, there were no significant differences in the postoperative survival in patients with stage II–IV disease. The rates of metastases to the distant peritoneum, M1, T4, a tumor size C5 cm and non-curative resection were higher in MC than in NMC patients.
S. Jimi (&) M. Hotokezaka T. Ikeda S. Uchiyama H. Hidaka N. Maehara H. Ishizaki K. Chijiiwa Department of Surgery 1, Miyazaki University School of Medicine, Miyazaki, Japan e-mail: [email protected] M. Hotokezaka Department of Surgery, Junwakai Memorial Hospital, Miyazaki, Japan
Conclusions Patients with MC had advanced stage cancer, especially with metastases to the distant peritoneum, more frequently than did the patients with NMC. To improve the survival of these patients, it is therefore important to detect MC at an early stage and to perform curative resection. Keywords Colorectal neoplasms Mucinous colorectal cancer Survival
Introduction Mucinous colorectal carcinoma (MC) is a histological subtype of colorectal cancer characterized by extracellular mucin production [1]. MC accounts for 5–15 % of all colorectal cancers [1–11]. MC is usually in a more advanced stage when it is diagnosed than well- or moderately differentiated adenocarcinoma, which is considered to be one reason for the worse prognosis of patients with MC than patients with non-mucinous colorectal carcinoma (NMC) [5, 8, 9, 12, 13]. However, the postoperative survival for MC patients in each stage is unclear, and the factors related to the survival of patients with MC have not been well studied. The aim of this retrospective study was to investigate the clinicopathological features and postoperative survival of patients with MC, and to identify the factors related to their long-term survival.
Patients and methods From 1991 to 2006, 446 patients at Miyazaki University Medical Hospital underwent surgery for colorectal carcinoma. Tumor resection for MC was confirmed in 26
123
Surg Today
patients, 23 of whom had verified survival data. The hospital maintains a database, and the medical records of all 23 patients were retrieved from this database. The database record includes data on the sex, age, past history, major medical problems, tumor location, maximum tumor size, histopathological stage, venous invasion and depth of wall invasion. The preoperative serum carcinoembryonic antigen (CEA) levels were obtained from the medical records. Data pertaining to the 23 MC patients were retrieved by reviewing the patients’ individual records, and variables were classified according to the TNM system [14]. The P factor refers to peritoneal metastasis, and was subclassified as follows: P0, no peritoneal metastasis; P1, metastasis localized in the adjacent peritoneum; P2, limited metastasis to the distant peritoneum and P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma [15]. P2 and P3 were both considered to indicate that the patient had metastasis to the distant peritoneum. The curability of surgical resection was determined at the end of surgery. When there was no residual cancer, the patient was determined to have undergone a curative surgery. When residual cancer was identified, then the patient was determined to have undergone non-curative surgery. Almost all patients returned to the hospital for followup. Telephone contact was made with patients, if necessary, to obtain up-to-date information. The effects of the clinicopathological variables, including the age, sex, number of metastatic lymph nodes, depth of wall invasion and preoperative serum CEA levels on survival were analyzed.
Statistical analyses The means were compared by Student’s t test, and 2 9 2 proportions were compared using Fisher’s exact test, while 8 9 2 and 4 9 2 proportions were tested by the v2 test [16]. The cancer-specific survival curves were generated using the Kaplan–Meier method [17]. To identify prognostic factors for survival, differences were compared by the log-rank test. A value of p \ 0.05 was considered to be significant. All statistical analyses were performed using the SPSS version 14.0J for Windows software program (SPSS Inc., Chicago, IL, USA).
Results In total, 23 patients with MC were included in the final analysis (14 males, 9 females; median age 65.7 years; age range 40–78 years). The mean follow-up period was 1,737 days (range 54–4,735 days). Cancer-related deaths
123
occurred in 12 cases. The 5-year cancer-specific survival rate was 56.2 %. Three patients could not be contacted because more than 5 years had passed since their surgeries. A total of 403 patients with NMC were included in the final analyses (269 males, 134 females; median age 65.7 years; age range 20–92 years). The mean follow-up period of the NMC patients was 2,293 days (range 7–4,677 days). Cancer-related deaths occurred in 121 cases. The 5-year cancer-specific survival rate was 73.8 %. A total of 17 patients could not be contacted because more than 5 years had passed since their surgeries. The overall compliance rate was 95.5 %. The background data were compared by Fisher’s exact test, the v2 test and Student’s t test, and the results are shown in Table 1. The rate of right-sided colon carcinoma was significantly higher in the MC than in the NMC group. The mean size of the tumor in the MC patients was 7.22 cm (range 3–20 cm); the mean size of the tumor in the NMC patients was 4.67 cm (range 0.5–28 cm). The mean size of the tumor was significantly greater in the MC patients than in the NMC patients (p = 0.008). There was also a significant difference in the rate of tumors larger than 5 cm between these groups. Nine MC patients had T4 tumors. Lymph node involvement was noted in 13 patients. Fifteen of the 23 patients presented at an advanced stage (five patients at stage III and 10 at stage IV). The rates of venous invasion, liver metastases and high CEA levels were not significantly different between the MC and NMC cases. Of the 23 patients with MC, 10 presented with distant metastases at the time of diagnosis. Nine patients had peritoneal dissemination, followed by liver metastases in five patients and a distant lymph node in one patient. The rates of T4 disease, the presence of peritoneal dissemination, M1 disease and advanced stage disease were significantly higher in the MC group than in the NMC group (Table 1). The rate of patients with non-curative resection was also higher in the MC than in the NMC patients. Peritoneal dissemination was usually classified by subtype according to the Japanese Classification of Colorectal Carcinoma. The 5-year survival rate of patients with P2 or P3 was 0 % in both the MC and NMC groups (Table 2). The 5-year survival rate of patients with P0 or P1 was also not significantly different between the MC and NMC groups (p = 0.302). The incidence of P2 or P3 disease was higher in the MC patients than in the NMC patients (Table 1). The results of a univariate analysis are shown in Table 3. The age, sex, location of the primary tumor, presence of venous invasion, preoperative serum CEA level, and size of the tumor had no significant effects on the survival. The univariate analysis showed that the presence
Surg Today Table 1 Clinical and pathological factors
Table 1 continued
MC (n = 23)
NMC (n = 403)
p value
Male
14
269
Female
9
134
0.355
65.7 (40–78)
65.7 (20–92)
0.987
Sex
Mean age (range, years)
15
242
C70 years
8
161
Right side
11
91
Left side
12
312
T1
0
50
T2
3
73
T3
11
219
T4
9
61
0.009
Tumor invasion depth
340
9
63
0.008
MC mucinous colorectal carcinoma, NMC non-mucinous colorectal carcinoma, CEA carcinoembryonic antigen The P factor was subclassified as follows: P0, no peritoneal metastasis, P1, metastasis localized to the adjacent peritoneum, P2, limited metastasis to the distant peritoneum or P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma b TNM, TNM classification of malignant tumors
No. of cases
0.012
5-year survival rate (%)
MC P0
14
78.6
P1
4
33.3
P2
1
0
355
P3
4
0
48
P0 or P1
18
71.8
P2 or P3
5
0
Negative
10
246
Positive
13
157
18 5
0.074
0.144
Peritoneal dissemination Negative
14
383
Positive
9
20
NMC \0.001
P factor subclassa P0 or P1
15
389
P2 or P3
5
14
Negative
13
334
Positive
10
69
I
1
109
II
7
123
III
5
99
10
72
0.021
Remote metastasis 0.004
TNM stageb
6
111
Positive
17
292
0.548
4.67 (0.5–28)
0.008
Maximum size of tumor (range, cm) 7.22 (3.0–20.0)
P0
383
77.0
P1
6
50.0
P2 P3
10 4
0 0
P0 or P1
389
76.3
P2 or P3
14
0
The P factor was subclassified as follows: P0, no peritoneal metastasis, P1, metastasis localized to the adjacent peritoneum, P2, limited metastasis to the distant peritoneum or P3, diffuse metastasis to the distant peritoneum, according to the Japan Classification of Colorectal Carcinoma
0.008
Negative
\5.0 cm
8
242
C5.0 cm
15
161
0.015
275 (2.0–5630)
175 (0.7–15184)
0.697
\5 ng/mL
8
196
C5 ng/mL
15
207
CEA
14
Non-curative
Table 2 The 5-year survival rates stratified by the P factor subclass
Lymph node metastasis
IV Venous invasion
Curative
p value
a
0.397
Location
Positive
NMC (n = 403)
Resection
\70 years
Liver metastasis Negative
MC (n = 23)
0.140
of T4 disease (p = 0.004), lymph node metastases (p = 0.044), liver metastases (p = 0.003), peritoneal dissemination (p \ 0.001), P2 or P3 disease (p \ 0.001), remote metastases (p \ 0.001), and curative resection (p \ 0.001) were significant factors affecting the survival. The 5-year overall cancer-specific survival rate was significantly worse in the MC patients (56.2 %) than in the well- or moderately differentiated NMC patients (73.8 %; p = 0.008) (Table 4). On the other hand, there was no significant difference in the postoperative survival in the patients with stage II, III and IV disease between the MC and NMC patients (Table 4). The survival of the patients in
123
Surg Today Table 3 The results of the univariate analysis for prognostic factors for mucinous carcinoma n
5-year survival (%)
Table 4 The survival of the MC and NMC patients stratified by stage n
5-year survival (%)
p value
p value Overall
Sex Male
MC 14
57.1
9
55.6
\70 years
15
59.3
C70 years
8
50.0
Location Right side
11
36.4
Left side
12
75.0
14
78.6
9
22.2
Negative
10
80.0
Positive
13
36.9
Negative
18
71.8
Positive
5
0.0
Female
NMC 0.783
Age
NMC
NMC
Tumor invasion depth T2 and T3 T4 Lymph node metastasis
0.008
1 109
100 96.1
Not assessed
7
100
123
82.5
0.170
5 99
60.0 79.5
0.182
MC
10
20.0
NMC
72
16.7
Stage III MC NMC
0.004
73.8
Stage II MC
0.162
56.2
Stage I MC
0.978
23 403
Stage IV 0.181
0.044
Liver metastasis 0.003
Peritoneal dissemination Negative
14
78.6
Positive
9
22.2
15
71.8
5
0
P factor subclass P0 or P1 P2 or P3
\0.001
\0.001
Remote metastasis Negative
13
84.6
Positive
10
20.0
\0.001
Venous invasion Negative
6
66.7
Positive
17
52.3
0.541
Maximum size of tumor \5.0 cm
8
33.3
C5.0 cm
15
66.7
\5 ng/mL
8
75.0
C5 ng/mL
15
40.0
0.067
14 9
85.7 0.0
\0.001
0.166
CEA
Resection Curative Non-curative
stage I could not be compared because there was only one MC case with stage I disease.
Discussion In this study, the clinicopathological features and survival of MC patients were assessed. The definition of MC is the
123
presence of a mucosal pool generated by the tumor. Symonds et al. [1] first reported that the tumors classified as MC were composed of glands secreting lakes of mucus deep within the infiltrating portion of the tumor. According to the WHO definition [18], MC is an adenocarcinoma in which a substantial amount of mucin ([50 % of the tumor) is retained within the tumor. The incidence of MC is about 5 % in Asian countries, such as Japan and Singapore [6–11], while the incidence of MC is about 10–15 % in Western countries [1–4, 19]. Because the 5-year survival rate of MC patients is 33–60 %, MC is considered to be a tumor with a poor prognosis [5, 8, 9, 12, 13]. However, there have been a few reports showing that the survival of MC patients was not significantly different from that of NMC patients [1, 4, 19]. In the present study, the overall 5-year survival rate of MC was 56.2 %, which was significantly worse than that for NMC. The overall survival of MC patients in each stage has not been adequately reported. Ikeda et al. [8] reported that the prognosis of MC was poorer than that of NMC at both stage II and stage III. Pihl et al. [3] reported the survival of Dukes A and C MC patients to be significantly worse than that of NMC patients. On the other hand, Consorti et al. and Berg et al. reported that there were no significant differences between MC and NMC patients at each stage [2, 20]. In the present study, there were no significant differences in the postoperative survival between MC and NMC patients in stages II, III and IV. The rate of patients in an advanced stage at presentation is high in primary MC cases [5, 8, 9]. Lymph node metastases or distant metastases are seen in most patients at the time of diagnosis [7, 21]. Spread throughout the
Surg Today
peritoneal cavity and lymph nodes is frequently seen, but distant hematogenous metastases, especially in the liver and lung, are uncommon [7]. The rate of stage III and stage IV disease was significantly higher in the MC than in the NMC patients in the present study (Fisher’s exact test). It has been suggested that the poorer prognosis of MC is related to the stage of the disease and to the extent of spread, but not to the mucinous histological type [5, 7–9, 19], and this appears to correlate with our present findings. The incidence of MC is higher in the right side of the colon than in the left side of the colon from the splenic flexure [2, 5, 22, 23]. Many reports have found that the incidence of MC was higher in younger patients than in older patients [4, 5, 11, 24, 25]. In the present study, there were no patients younger than 40 years, but there was a higher rate of right-sided cancer in the MC group than in the NMC group. In our previous report, the patients with P0 or P1 dissemination survived longer after surgery than did the patients with peritoneal metastasis, who were classified as P2 or P3 [26]. In the present study, the 5-year survival rate of the patients classified as P2 or P3 was 0 % in both the MC and NMC groups. The 5-year survival rate of the patients classified as P0 or P1 was also not significantly different between the MC and NMC groups. The incidence of P2 or P3 disease was higher in the MC than in the NMC groups (p = 0.021). Patients with MC more frequently had peritoneal metastasis to the distant peritoneum than did the patients with NMC, and thus the patients with MC had a worse prognosis than the patients with NMC, even though there were no significant differences between the patients in the two groups in each stage (for stages II–IV). The present univariate analyses identified five significant prognostic factors for the survival of patients with MC: the depth of tumor wall invasion (T factor), presence of lymph node metastases, presence of liver metastases, presence of peritoneal dissemination and the presence of non-curable remote metastases (M factor). The CEA level and the size of the primary tumor were not prognostic factors for the MC group. Although the tumor size was significantly larger in the MC patients than in the NMC patients (Student’s t test and Fisher’s exact test), the tumor size was not a prognostic factor for MC in the univariate analyses in the present study. Kubota et al. [10] also reported that liver metastases and the depth of tumor invasion were prognostic factors for MC. MC of the rectum demonstrates a poorer response to standard preoperative chemoradiotherapy than NMC [27]. However, recent advances in adjuvant chemotherapy have further improved the disease-free survival after curative surgery for colon cancer [28], but an effective regimen for MC has not yet been found.
The postoperative survival was not significantly worse for the MC patients than for the NMC patients in each stage. However, the patients with MC had advanced stage cancer, especially with advanced peritoneal dissemination, more frequently than did the patients with NMC at the time of diagnosis. This seems to be an important factor associated with the poor prognosis after surgery in patients with MC. To improve the survival of these patients, it is important to detect MC at an early stage and to perform curative resection. Conflict of interest conflicts of interest.
Sei-ichiro Jimi and the co-authors have no
References 1. Symonds DA, Vickery AL. Mucinous carcinoma of the colon and rectum. Cancer. 1976;37:1891–900. 2. Consorti F, Lorenzotti A, Midiri G, Paola M. Prognostic significance of mucinous carcinoma of colon and rectum: a prospective case–control study. J Surg Oncol. 2000;73:70–4. 3. Pihl E, Narin RC, Hughes ESR, Cuthbertson AM, Rollo AJ. Mucinous colorectal carcinoma immunopathology and prognosis. Pathology. 1980;12:439–47. 4. Minsky BD, Mies C, Rich TA, Recht A, Chaffey JT. Colloid carcinoma of the colon and rectum. Cancer. 1987;60: 3103–12. 5. Wu CS, Tung SY, Chen PC, Kuo YC. Clinicopathological study of colorectal mucinous carcinoma in Taiwan: a multivariate analysis. J Gastroenterol Hepatol. 1996;11:77–81. 6. Kanemitsu Y, Kato T, Hirai T, Yasui K, Morimoto T, Shimizu Y, et al. Survival after curative resection for mucinous adenocarcinoma of the colorectum. Dis Colon Rectum. 2003;46: 160–7. 7. Yamamoto S, Mochizuki H, Hase K, Yamamoto T, Ohkusa Y, Yokoyama S, et al. Assessment of clinicopathological features of colorectal mucinous adenocarcinoma. Am J Surg. 1993;166: 257–61. 8. Ikeda S, Shimizu Y, Fujimori M, Ishizaki Y, Kurihara T, Okajima T, et al. Immunohistochemical and mutational analyses of betacatenin, ki-ras, and p53 in two subtypes of colorectal mucinous carcinoma. Clin Cancer Res. 2003;9:5660–5. 9. Nozoe T, Anai H, Nasu S, Sugimachi K. Clinicopathological characteristics of mucinous carcinoma of the colon and rectum. J Surg Oncol. 2000;75:103–7. 10. Kubota K, Akasu T, Fujita S, Sugihara K, Moriya Y, Yamamoto S. Clinical and pathological prognostic indicator with colorectal mucinous carcinomas. Hepatogastroenterology. 2004;51:142–6. 11. Du W, Mah JT, Lee J, Sankila R, Sankaranarayanan R, Chia KS. Incidence and survival of mucinous adenocarcinoma of the colorectum: a population-based study from an Asian country. Dis Colon Rectum. 2004;47:78–85. 12. Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JB Jr, Ray JE. Mucinous carcinoma: just another colon cancer? Dis Colon Rectum. 1993;36:49–54. 13. Okuno M, Ikehara T, Nagayama M, Kato Y, Yui S, Umeyama K. Mucinous colorectal carcinoma: clinical pathology and prognosis. Am Surg. 1988;54:681–5. 14. Sobin LH, Gospodarowicz MK, Wittekind CH, editors. TNM classification of malignant tumours (UICC). 7th ed. West Sussex: Wiley; 2009.
123
Surg Today 15. Japanese Society for Cancer of the Colon and Rectum, editors. Japan Classification of colorectal carcinoma. 2nd English ed. Tokyo: Kanehara &Co., Ltd; 2009. 16. Agresti A. A survey of exact inference for contingency tables. Stat Sci. 1992;7:131–77. 17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81. 18. Jass JR, Sobin LH. Histological type of intestinal tumors. Berlin: Springer-Verlag; 1989. 19. Umpleby HC, Ranson DL, Williamson RCN. Peculiarities of mucinous colorectal carcinoma. Br J Surg. 1985;72:715–8. 20. Berg JW, Godwin JD. The epidemiologic pathology of carcinoma of the large bowel. J Surg Oncol. 1974;6:381–400. 21. Parham D. Colloid carcinoma. Ann Surg. 1923;77:90–105. 22. Leopoldo S, Lorena B, Cinzia A, Gabriella DC, Luciana BA, Renato C, et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann Surg Oncol. 2008;15:1429–39.
123
23. Halvorsen TB, Seim E. Influence of mucinous components on survival in colorectal adenocarcinomas: a multivariant analysis. J Clin Pathol. 1988;41:1068–72. 24. Messerini L, Ciantelli M, Baglioni S, Palomba A, Zampi G, Papi L. Prognostic significance of microsatellite instability in sporadic mucinous colorectal cancers. Hum Pathol. 1999;30:629–34. 25. Keswani SG, Bolye MJ, Maxwell JP 4th, Mains L, Wilks SM, Hunt JP, et al. Colorectal cancer in patients younger than 40 years of age. Am Surg. 2002;68:871–6. 26. Hotokezaka M, Jimi S-I, Hidaka H, Ikeda T, Uchiyama S, Nakashima S, et al. Factors influencing outcome after surgery for stage IV colorectal cancer. Surg Today. 2008;38:784–9. 27. Shin US, Yu CS, Kim JH, Kim TW, Lim SB, Yoon SN, et al. Mucinous rectal cancer: effectiveness of preoperative chemoradiotherapy and prognosis. Ann Surg Oncol. 2011;18:2232–9. 28. Andre T, Cormier JN, Krishnan S, Yao J, Staerkel GA, Lupo PJ, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.
